ABSTRACT Responding to PAR 17-029: Dynamic Interactions between systemic or non-neuronal systems and the brain in aging and in AD, this proposal will elucidate the mechanisms underlying impaired mobility, an understudied phenotype as highlighted by NIA workshops, Aging, the CNS, and Mobility. The pathologies causing AD and related disorders, such as Lewy bodies and cerebrovascular disease cause impaired mobility. Yet, pathologies only account for a minority of its variance, underscoring the need to identify molecular drivers without a known pathologic footprint. The molecular drivers of mobility are unknown, but can be located in any of the key motor tissues crucial for mobility. This study will elucidate the molecular drivers (genes and their proteins) of impaired mobility in AD and related disorders in key motor tissues within and outside the CNS. This postmortem study will leverage novel clinical and postmortem resources from older participants of the Rush Memory and Aging Project (R01AG17917). A systems biology approach will be applied to new gene expression data obtained from brain, spinal cord and muscle, all tissues crucial for mobility (Aim1). Tissues will come from the same persons, all of whom had instrumented gait testing with a body-sensor proximate to death. In each motor region, we will identify the molecular systems associated with AD and related pathologies and mobility (Aim 2). Causal network inference will be used to identify influential genes and cross-tissue signaling (Aim 3). Validating protein levels of influential genes in each motor region increases the scientific rigor and translational impact of this study by providing a high-confidence list of genes driving impaired mobility in older adults (Aim 4). Compelling preliminary studies support this study. 1) AD and related pathologies extend to spinal cord and are related to poorer mobility, highlighting the need to examine these tissues. 2) The limited explanatory power of AD and related pathologies for mobility underscores the need to seek molecular systems without a pathologic footprint that drive mobility. 3) Whole genome transcriptome were obtained from brain, spinal cord and muscle samples and gene expression levels were related to gait. 4) A system biology approach followed by protein validation has been informative in studies of cognition. This study will provide a comprehensive description of the pathologies and molecular drivers of impaired mobility in AD and related disorders. Confirming specific genes and proteins that drive impaired mobility provides a means to move beyond descriptive studies, delivering a list of gene that can be targeted in drug development and intervention studies. Thus, this proposal has potential to make a sustained impact on aging research and inform on efforts to reduce a major adverse health consequence of aging, AD and related disorders in millions of older Americans.